PROJECT SUMMARY/ABSTRACT This proposed effort is offered in response to NIH Funding Opportunity Announcement (FOA) Number PAR-16-370: Phenotypic and Functional Characterization of ApoE2 to Inform Translation Strategies for Aging-Related Conditions. This FOA encourages a focus on the Apolipoprotein E 2 allele in the belief that understanding mechanisms responsible for its apparent protective influence may improve our understanding of why some persons escape the vascular and neurodegenerative ravages of brain aging, while others suffer impairments and a shortening of their productive lives. Our application addresses a specific hypothesis: that the several health and aging phenotypes linked to the individual ApoE alleles are differentially modified or mediated by other genetic factors that travel with each ApoE allele by virtue of their contiguity on chromosome 19. Instead of limiting analyses to the ApoE alleles by themselves, we will examine and compare the conjoint influences of the ApoE2, ApoE3, and ApoE4 alleles, each with two other genes and several other genetic polymorphisms, linked by common membership in a limited number of haplotypes. The associations of those haplotypes and constituent genes with clinical, functional, and neuropathologic indicators of pathologic brain aging will be examined in deceased participants from three longitudinally studied cohorts ? the Honolulu-Asia Aging Study, the 90+ Study, and the University of California San Diego Alzheimer's project.